Diabetes is characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. There are two types of diabetes. Type 1 diabetes is usually diagnosed in children and young adults, and was previously known as juvenile diabetes. In type 1 diabetes, the body does not produce insulin. Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Patients with type 2 diabetes are at increased risk of macro vascular and micro vascular complications, including coronary artery disease, stroke, hypertension, nephropathy, peripheral vascular disease, neuropathy, and retinopathy.
A significant, rapidly growing fraction of the human population is affected by type 2 diabetes, a disease characterized by elevated blood glucose levels and relative insufficiency of insulin. Recently researches found that the activity of two potent stimulators of insulin secretion, GLP-1 and GIP, is rapidly abolished by the serine peptidase dipeptidyl peptidase IV (DPP-IV). DPP-IV is a member of a family of serine peptidases. CD26 or DPP-IV is a membrane-associated peptidase of 766 amino acids that is widely distributed in numerous tissues. DPP-4 also exists as a soluble circulating form in plasma and significant DPP-4-like activity is detectable in plasma from humans and rodents. The principal biological activity of CD26 (DPP-IV) is its enzymatic function. DPP-IV prefers substrates with an amino-terminal proline or alanine at position 2, but may also cleave substrates with non-preferred amino acids at position 2. The structure of GIP, GLP-1 and GLP-2 reveals a highly conserved alanine at position 2, rendering these peptides ideal putative substrates for the aminopeptidase dipeptidyl peptidase 4 (DPP-4). Eur J Biochem. 1993, 214(3), 829-35.
A glance at the available treatments for type 2 diabetes, which have not changed substantially in many years, makes clear that they all have their own limitations. There are many pharmacologic strategies to accomplish these goals. First of this series are alpha glucosidase inhibitors such as acarbose and miglitol, which function by interfering with the action of the alpha-glucosidases present in the small intestinal brush border. The consequence of this inhibition is a reduction in digestion and the consequent absorption of glucose into the systemic circulation. The reduction in glucose uptake allows the pancreatic beta-cells to regulate the insulin secretion more effectively. The advantage of the use of the alpha-glucosidase inhibitors is that they function locally in the intestine and have no major systemic action. Hypoglycemia does not usually occur with the use of alpha-glucosidase inhibitors but they are effective in reducing fasting plasma glucose (FPG) levels and levels of glycosylated hemoglobin (HbA1c). The common adverse side effects of these inhibitors are abdominal bloating and discomfort, diarrhea, and flatulence.
The sulfonylureas and meglitinide classes of oral hypoglycemic drugs are referred to as endogenous insulin secretagogues because they induce the pancreatic release of endogenous insulin. Because these drugs can induce pronounced hypoglycemia, treatment is initiated with the lowest possible dose and carefully monitored until the dose results in a FPG of 110-140 mg/dL. Sulfonylureas function by binding to and inhibiting the pancreatic ATP-dependent potassium channel that is normally involved in glucose-mediated insulin secretion. Sulfonylureas have no significant effects on circulating triglycerides, lipoproteins, or cholesterol. The non-sulfonylurea insulin secretagogues are both fast acting and of short duration. However, meglitinides (non-sulfonylurea insulin secretagogues) do exert effects on potassium conductance. Like the sulfonylureas, the meglitinides have no direct effects on the circulating levels of plasma lipids.
The biguanides lower serum glucose levels by enhancing insulin-mediated suppression of hepatic glucose production and enhancing insulin-stimulated glucose uptake by skeletal muscle. Metformin is a member of this class and is currently the most widely prescribed insulin-sensitizing drug in clinical use. Metformin administration does not lead to increased insulin release from the pancreas and as such the risk of hypoglycemia is minimal. Because the major site of action for metformin is the liver its use can be contraindicated in patients with liver dysfunction. In adolescent females with type 2 diabetes, the use of metformin is highly recommended to reduce the incidence as well as the potential for polycystic ovarian syndrome. However the two biguanides, phenformin and metformin can induce lactic acidosis and nausea/diarrhea.
The peroxisome proliferator-activated nuclear receptor (PPAR) family has received particular scrutiny in the field of diabetes and as a result the thiazolidinediones have emerged as a therapeutic class. First generation thiazolidinediones were agonists of the PPAR gamma receptor and were able to reduce insulin resistance. One adverse effect associated with PPAR gamma receptor agonists is however weight gain. More recently molecules have been developed that activate PPAR alpha. This class is able to reduce triglyceride levels and is also able to improve insulin sensitivity and as a result dual PPAR alpha/PPAR gamma agonists have been developed with proposed beneficial effects over existing PPAR gamma- and alpha-preferential drugs in treatment of type 2 diabetes. But safety issues slowed down the entry of these drugs
One of the exciting classes of agents in development are GLP-1 agonists. The primary metabolic responses to GLP-1 release from the enteroendocrine L-cells of the gut are inhibition of glucagon secretion and enhancement of glucose-dependent insulin release from the pancreas, both effects lead to decreased glycemic excursion. But the hormonal action of GLP-1 is rapidly terminated as a consequence of enzymatic cleavage by DPP IV. Recent clinical evidence has shown that either infusion of GLP-1 or inhibition of DPP IV can result in dramatic reductions in plasma glucose concentrations, reductions in HbA1c, and improvement in pancreatic beta-cell function. Thus, both represent potential targets for the prevention of the hyperglycemia associated with diabetes and impaired insulin function. There are advantages and disadvantages with the current therapeutic approaches targeting GLP-1 action in diabetic patients. Current use of GLP-1 mimetics and/or GLP-1 receptor (GLP-1R) agonists focus on peptides or modified peptides and these must be given by injection, which leads to problems with the patient-compliance.
Another novel mechanism for the treatment of type 2 diabetes are Dipeptidyl peptidase-IV inhibitors. Dipeptidyl peptidase IV is a multifunctional protein involved in cleaving incretin hormones, hence serving to regulate glucose homeostasis and consequently viewed as a target for the management of Type 2 diabetes. The usefulness of Dipeptidyl peptidase IV in the treatment of Type 2 diabetes is based on the fact that Dipeptidyl peptidase IV in vivo readily inactivates GLP-1 and GIP. These are the incretins that are produced when food is consumed. These incretins stimulate production of insulin. Inhibition of Dipeptidyl peptidase IV leads to decreased inactivation of incretins, in turn increased efficacy of incretins in stimulating insulin production by pancreas. Therefore Dipeptidyl peptidase IV inhibition results in an increased level of serum insulin. An interesting observation is that incretins are produced only when food is consumed. So the Dipeptidyl peptidase IV inhibition is not expected to increase the level of insulin between meals which can lead to hypoglycemia. Inhibition of Dipeptidyl peptidase IV is therefore expected to increase insulin without increasing the risk of hypoglycemia. Investigational Dipeptidyl peptidase IV inhibitors offer an advantage over other novel therapies since they can be administered orally. Compliance in patients is much higher with orally delivered drugs than with those that require injection. Thus Dipeptidyl peptidase IV inhibitors are a promising new approach to treat type 2 diabetes, which function, at least in part, as indirect stimulators of insulin secretion. Mechanism and use of DPPIV inhibitors in various diseases is well explained in prior art patents like WO 2005/033106 and is herein incorporated by reference in its entirety.